The development of a topical form of aspirin has long been an objective of the formulator of pharmaceutical products and the fact that none exists today, is an indication of the difficulty of its fulfillment. In the minds of many experts, aspirin is still the drug of choice for the treatment of arthritis but the well known gastric irritation it produces, especially when taken in the large doses required for arthritis relief, remains the major bar to its more widespread use.
The major motivation for the development and success in the marketplace for acetaminophen and the host of non-steroidal anti-inflammatory drugs has been the hope of finding a mild analgesic without the gastric irritation produced by aspirin.
It is obvious that an effective topical form of aspirin would eliminate its gastric side effects. It is also accepted that the application locally of effective concentrations of aspirin could be effective in the treatment of musculoskeletal pain as in arthritis. Aspirin has been shown to be adsorbed into and through the skin and in fact the skin has been shown to be a reservoir for topically applied aspirin.
It is also known that aspirin is a more potent analgesic, anti-inflammatory agent than the other salicylates, e.g., methyl salicylate or triethanolamine salicylate which are the salicylates commonly used in topical analgesic products.
The major deterrent to the use of topical aspirin is that a stable aspirin solution has heretofore been impossible to prepare. Aspirin is not stable in aqueous solutions nor in any of the common solvents used in topical pharmaceuticals such as the glycols or lower aliphatic alcohols. It is rapidly hydrolyzed to acetic and salicylic acids and thus its shelf life in such solvents is far too short to permit the development of a stable aspirin solution suitable for marketing. Water alone is not the only contributor to aspirin degradation in solution. Aspirin will degrade by hydrolysis, glycolysis and trans-esterification, all of which will be promoted by any pH higher than about 3.5.
Solvents, such as N,N-Diethyl-m-Toluamide USP (DEET) and mixtures of N,N-Diethyl-m-Toluamide USP and Gyceryl Triacetate USP (GTA) give clear solutions of aspirin suitable for topical application to humans, in and of themselves, but both solvents cause aspirin to degrade to an unacceptable degree.
Both the DEET and glyceryl triacetate, if absolutely pure, would theoretically be unreactive to aspirin, but in reality, both these solvents as commercially available, contain impurities. The DEET is commercially available at about 97% active with the balance being isomers of DEET that have been identified as follows:
Methylbenzyl Alcohol PA0 N,N,-Diethylbenzamide PA0 N,-Ethyl Toluamide PA0 N,N,-Diethyl-o-Toluamide PA0 N,N,-Diethyl-p-Toluamide PA0 Trimethyl biphenyl PA0 Tetramethylbiphenyl
These impurities are reactive to aspirin causing its degradation.
The glyceryl triacetate usually contains trace quantities of water and mono and diacetates of glycerine, all of which degrade aspirin.